Researchers of two independent studies have discovered how a specific mutation on the TREM2 gene contributes to the development and progression of Alzheimer’s disease, findings that shed light on the role of TREM2 in the brain, and can lead to new ways of treating this neurological disease.
Their work was reported in studies titled “TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant” and “An Alzheimer associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function,” both published in the journal EMBO Molecular Medicine.
Specialized immune cells called microglia are responsible for protecting the brain from damage caused by toxic components like amyloid-β aggregates or dying cells. But aging or the onset of a neurological diseases cause microglia to lose their protective abilities, so that they fail to clear the brain of damaging materials.
The TREM2 gene encodes for a protein — also known as TREM2, for triggering receptor expressed on myeloid cells 2 — that aids microglia in its protective role. This receptor is expressed on the surface of microglia cells, so as to detect toxic elements or dying cells. When lipid aggregates or other threats are found, the receptor cleaves in two and promotes degradation and clearance of the threat.
Both studies found that this cleaving of the TREM2 protein is altered in Alzheimer’s due to a rare genetic mutation on the 157 position of the gene, or a mutation known as p.H157Y. This genetic variant is known to researchers. Indeed, scientists in China demonstrated in a large-scale study published in 2016 that the p.H157Y mutation on TREM2 was associated with susceptibility to late-onset Alzheimer’s disease.
Led by Christian Haass at the German Center for Neurodegenerative Diseases at the Ludwig-Maximilians-Universität in Munich, and by Damian Crowther of AstraZeneca’s IMED Neuroscience group in Cambridge, the two teams both demonstrated that the presence of the p.H157Y gene variant led to a more rapid cleavage of the TREM2 receptor than is normal, preventing microglia cells from fully recognizing amyloid-β aggregates and dying cells.
“Our results provide a detailed molecular mechanism for how this rare mutation alters the function of TREM2 and hence facilitates the progression of Alzheimer’s disease,” Crowther said in a news release.
In contrast to other genetic mutations, that seen in p.H157Y does not change the levels of the active protein, but instead prevents it from working as it should. This suggests that developing ways to promote the protein’s stability may help to prevent it from cutting into two parts too quickly, allowing microglia to better protect the brain from toxic buildup.
“The end result is the same. In both cases, there is too little full-length TREM protein on microglia,” Haass said. “This suggests that stabilizing TREM2, by making it less susceptible to cleavage, may be a viable therapeutic strategy.”
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